Bacteriology of the Complex Genus Salmonella. Only two species are currently recognized within the genus Salmonella, Salmonella enterica and Salmonella bongori, and only the former is important with respect to human disease. There are six subspecies of Salmonella enterica, of which subspecies I, S. enterica subspecies enterica, contains all the important pathogens that cause human disease. S. enterica subspecies enterica is further sub-divided into more than 2500 serovars (i.e., distinct serotypes) based on the presence of specific somatic O antigens, capsular polysaccharide surface Vi antigen and flagellar H antigens expressed by the organism. The antigenic serotyping scheme (previously called the Kauffman-White scheme and more recently the White-Kauffmann-Le Minor scheme) defines a serovar (i.e., serotype) by its O polysaccharide antigens (and also whether capsular polysaccharide Vi is expressed) and its H flagella antigens. The serogroup of a Salmonella is defined by its O antigens, while the serovar is defined by the full antigenic structure that includes all the flagellar antigens and whether Vi polysaccharide is expressed. O antigens are part of the lipopolysaccharide (LPS) surface structure that is part of the outer membrane of the bacteria. The lipid A (endotoxin) portion of the LPS, is a glucosamine-based phospholipid that makes up the outer monolayer of the outer membrane of the bacteria. Attached to the lipid A is a core polysaccharide that is essentially identical in all the important Salmonella serovars that cause human disease, particularly invasive disease. The more internal portion of the core polysaccharide is the “inner core”, while the more external portion is the “outer core” (FIG. 1). Finally, the most external surface component that is attached to the outer core polysaccharide is a terminal O polysaccharide that consists of terminal O repeat units linked one to another; this is what is exposed to the environment. The terminal O polysaccharide varies in structure depending on the sugars comprising the core unit and their linkages one to another. Many of the most important Salmonella serovars associated with human disease fall into serogroup B and serogroup D. The O repeat units of Salmonella serogroups B and D share a common trisaccharide backbone that consists of repeats of mannose-rhamnose and galactose (Wyk P and Reeves P. J. Bacteriol. 1989; 171:5687-5693). This backbone is the structure for the common Salmonella epitope 12 that is found in serogroup A, B and Group D Attached to the backbone is another dideoxyhexose sugar that is alpha 1,3-linked to the mannose residue. If that dideoxyhexose sugar is abequose, the resultant structure constitutes the immunodominant antigen “4” that defines O serogroup B. If the dideoxyhexose sugar that is alpha 1,3-linked to mannose is tyvelose, the resultant structure creates immunodominant antigen “9” that defines O serogroup D.
Some Salmonella can express two different antigenic forms of flagella, called Phase 1 and Phase 2. Salmonella Typhimurium has the antigenic scheme 1,4,(5),12:i:1,2. This indicates that it falls within O serogroup B (defined by antigen 4), expresses minor O antigens 1 and 12 and sometimes antigen 5 and expresses Phase 1 flagella which manifest antigen H:i and Phase 2 flagella which manifest antigen H:1,2.
Treatment of Salmonella infection continues to be a major public health burden and represents a very significant cost in many countries, particularly countries without adequate access to effective antibiotics or medical care. Millions of human cases are reported worldwide every year and the disease results in thousands of deaths.
In recent years problems related to Salmonella infection have increased in terms of incidence and severity. Of particular concern is the emergence of Salmonella strains that are resistant to a range of antibiotics.
Thus, there remains a need for a broad spectrum Salmonella enterica vaccine that is effective against typhoidal and non-typhoidal Salmonella. The present invention provides multivalent conjugate vaccines directed against various Salmonella enterica serovars as well as engineered attenuated Salmonella enterica serovars for use in vaccines and as reagent strains to produce the multivalent conjugate vaccines of the invention.